Sustained release preparations are useful preparations which are capable of decreasing frequency of administration and controlling concentrations of medicinal agents in blood so as to maintain medicinal effects. For example, use of a sustained release preparation can decrease administration frequency of a medicinal agent such as ibuprofen (half-life period: 2 hours) or phenylpropanolamine hydrochloride (half-life period: 4 hours) from three times per day (ordinarily necessary times) to twice per day. Moreover, use of a sustained release preparation can control the concentration of a medicinal agent such as theophylline in blood, which agent is narrow in concentration range wherein medicinal effects are exerted or side effects occur, so as to attain reduction of side effects and long duration of medicinal effects. As one approach for attaining such a sustained release preparation, hydrogel bases using water soluble polymers as sustained release bases are proposed (Patent Documents 1 to 4).
4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone (hereinafter abbreviated as “compound A”) or a pharmaceutically acceptable salt thereof is a compound which has an inhibitory effect against phosphodiesterase III enzymes, and has shown great promise as a therapeutic medicine for a disease such as asthma (Patent Document 5). However, this compound is greatly influenced by first pass effect through liver and has a very short half-life period of about 1.5 hours in blood plasma. Furthermore, since it is known that phosphodiesterase III enzymes exist in many internal organs, the concentrations of the compound in blood plasma are required to be controlled appropriately so as to attain its activity and avoid occurrence of side effects simultaneously. Therefore, it is preferable that a sustained release preparation for compound A or its pharmaceutically acceptable salt lowers the maximum concentration in blood plasma (Cmax) of compound A and maintains the effective concentration in blood plasma for a long period of time.
On the other hand, a pharmaceutically acceptable salt of compound A decreases its solubility in water at a pH range of about 4.0 or higher, and becomes quite poorly soluble around at a neutral pH range which is similar to enteric environment. As a result, there arise problems that a preparation containing a pharmaceutically acceptable salt of compound A is poor in dissolution after oral administration and is low in absorbability to dogs, i.e., bioavailability in a fasting state is about 10%. For improving such a poor dissolution and absorbability, it has been found that an organic acid such as citric acid, tartaric acid, malic acid, fumaric acid, malonic acid, succinic acid or maleic acid is present together with a pharmaceutically acceptable salt of compound A to obtain a preparation which attains immediate release (Patent Document 6). It has also been found that, when an organic acid such as citric acid, tartaric acid, malic acid, fumaric acid, malonic acid, succinic acid or maleic acid is present together with a pharmaceutically acceptable salt of compound A, and a hydrogel base such as a carboxyvinyl polymer is blended therewith, dissolution of compound A from the preparation can be controlled independently upon pH (Patent Document 7). However, the thus obtained preparation merely delays the time-to-maximum plasma concentration (Tmax) of compound A, and is insufficient in properties required of a sustained release preparation, i.e., reduction of Cmax and maintenance of the effective concentration in blood plasma.